Organoseleno cytostatic derivatives: Autophagic cell death with AMPK and JNK activation

Abstract

Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines.Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI 50 values below 10 µM. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death.Consistent with autophagy, increased Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers.

New Amides and Phosphoramidates Containing Selenium: Studies on Their Cytotoxicity and Antioxidant Activities in Breast Cancer

“…In addition, the autophagic flux, SQSTM1/p62, was downregulated confirming the autophagy process. Phosphorylation of AMPK and JNK was also studied because they have shown to be implicated in autophagy-mediated cell death [27]. As expected, both compounds induced JNK and AMPK phosphorylation.…”

“…Accumulating evidence in the literature has illustrated that among the different selenated scaffolds, selenenocyanate [19,20] and diselenide [21][22][23] fragments are important pharmacophores that significantly suppress breast cancer. Furthermore, our research group has reported that selenocyanate and diselenide entities possess potent antitumor activity [24][25][26][27]. Consequently, these motifs are considered as an encouraging template for designing a new category of selenium compounds.…”

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

“…Recently, the organoseleno derivatives (Figure , compounds 1 and 2 ) have been reported to trigger ADCD in human breast carcinoma MCF-7 cells by activating AMPK and JNK pathway, as well as increasing beclin-1 and LC3II and reducing p62 levels . Moreover, compound 1 and compound 2 induced cell death could be repressed by autophagy inhibitors (wortmannin and chloroquine) but could not be affected by the caspase inhibitor (Z-VAD-FMK) . It is suggested that ADCD is the way by which compound 1 and compound 2 may cause their effects .…”

“…Moreover, compound 1 and compound 2 induced cell death could be repressed by autophagy inhibitors (wortmannin and chloroquine) but could not be affected by the caspase inhibitor (Z-VAD-FMK) . It is suggested that ADCD is the way by which compound 1 and compound 2 may cause their effects . Fluorinated thiazolidionol (Figure , compound 3 ) can induce AMPK activation and inhibit PI3K/AKT/mTORC1 and MEK/ERK pathways, triggering ADCD in pancreatic ductal adenocarcinoma MIA PaCa-2 and PANC-1 cells proved by increased cytoplasmic vacuoles formation and enhanced autophagic flux .…”

“…9 The vacuolar protein sorting 34 (VPS34)-beclin-1 complex is also the key regulator of autophagy, and the upregulation of beclin-1 expression promotes ADCD. 13 Further, prolonged activation of the protein kinases that cause cytoprotective autophagy can also induce ADCD, such as C-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK), 14,15 which can stimulate autophagy by modulating beclin-1 expression. Nevertheless, since autophagy is a doubleedged sword with both prosurvival and prodeath properties, 9 whether inducing hyperactivation of autophagy could evoke more complicated cellular responses beyond regulating cell death progress has yet to be established.…”